The SCOR will investigate the pathogenesis of CF lung disease. The Projects will focus on potential links between abnormal electrolyte transport and lung infection. Two major contrasting views of CF pathogenesis will be tested: 1) the isotonic volume hypothesis; and 2) the hypotonic ASL hypothesis. To differentiate between these hypothesis, novel cell biologic, biochemical, physiologic, gene targeted mice, and clinical studies are required to: 1) fill in gaps in our understanding of normal airway epithelial functions; and 2) test the effects of abnormal CFTR function on this physiology. Project I (RCB, P.I.) will distinguish between airway epithelia as volume transporters versus ionic composition regulators, by generating a balance sheet describing ion and water flows transepithelially in small and large airways and within the airway tree by testing whether ASL moves axially, followed by studies of the effects of mutations in CFTR on these processes. Project II (MJS) will generate "topographical" information on the organization of CFTR and its PKA regulators in the apical membrane. The goals will be to understand whether specific PKA regulation of basal C1-conductance exists and how PKA-CFTR- mediated regulation of other transport proteins occurs. Project III (BHK, P.I.) focuses on the general issue of the protective effects of C1- permeability in the lung. This project tests the hypothesis that molecularly deletion in mice a key protein that mediates transcellular Cl- flow (the Na+-K+-2Cl-co transporter) will reduce Cl-flows in mouse airways, render non-functional Cl-/a, and lead to lung disease. Project IV (MRK, P.I.) will measure normal epithelial function and CF pathogenesis in newborns, measuring ASL ion composition and testing the predictions of each hypothesis by measuring the sequence of mucin plugging and infection. The SCOR is supported by 4 Cores: Administrative (A), Cell Culture (B), Analytic (C), and Morphology (D). The goals of SCOR are to provide a comprehensive description of the metabolism of ASL and the CF-specific abnormalities in ASL metabolism so that novel therapies and surrogate markers for such therapies can be developed for CF lung disease.